Proposal Summary Evaluation of lifespan and healthspan remain a cornerstone of documenting efficacy in aging research. However, it is becoming increasingly appreciated that housing rodents in conventional, unprovoked conditions, rather than exposed to the same variety of stressors normally encountered by free-living humans, has limited our understanding of how these strategies can be most effectively translated to humans. As defined in this RFA resilience is the ability in which an organism can respond to a physical challenge or stress and return to homeostasis. Physiologic resilience declines with age and can contribute to, and may underlie the onset of aging-related conditions. Thus, resilience in early or mid-life may be predictive of future healthspan and longevity. Thus, development of a simple, short-term battery of assays to characterize resilience in rodents could revolutionize aging research by enabling a rapid, inexpensive and comprehensive strategy to diagnose intervention efficacy, with possible prediction value for future outcomes. Therefore, we propose a battery of simple, diverse challenges and assays to include elective surgery, radiation, starvation, and an infection model to characterize resilience in rodents with the goal of predicting future outcomes. We hypothesize that exceptional resilience is requisite to healthy aging and longevity, and that assays optimized to detect variation in resilience can be prognostic of long-term aging outcomes. In Aim 1, we will establish and optimize a battery of functional tests to distinguish changes in physiologic resilience with aging in CB6F1 male and female mice. The goal of this aim is to calibrate both the application and detection of responses to stressors with well- established human homologues (radiation, starvation, surgery, and infection) and straight-forward response assays (i.e. body weight, temperature, etc) in mice at 4, 12, and 20 mo of age. We will consider implementation successful with observed age sensitivity to the stressor and increasing intra-group variability in the response with advancing age, which will confirm the potential for discriminating good, average and poor responders as a predictor of outcomes in Aim 2. In Aim 2, we will determine the ability of resilience at 12 mo of age to predict future healthspan across multiple domains (cognitive, cardiovascular, neuromuscular, metabolic) as well as longevity. In Aim 3, we will determine if pharmacologic interventions with demonstrated sexually-dimorphic effects on aging outcomes confer similar sex differences in physiologic resilience. This Aim will attempt to validate the ability of optimized tests of resilience to interventions that modulate lifespan by focusing on two pharmacologic strategies with striking sex differences on survival. To that end, 16 mo old male and female mice for 4 mo with 17?-estradiol, which preferentially favors males, and IGF-1R mAb, which favors females, and determine if sex-specific improvements in resilience can be detected using our optimized battery of assays. Development, refinement, and validation of easily performed assays of resilience will not only help address an important gap in aging research, but will have a major impact on how pre-clinical aging studies are conducted in the future.